This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California San Diego in consortium with The Buck Institute. The major goals of the Center over the next five years will be to expand our efforts into studying the conversion from normal aging to dementia through the intermediary step of Mild Cognitive Impairment (MCI) and to study mechanisms of neurodegeneration Projects will focus on functional MRI of the elderly at risk for Alzheimer's disease (Bondi, Project 1), testing of the role of axonal disturbances in Alzheimer's disease (Goldstein, Project 2), and studying the cytoplasmic domain of APP and its interacting proteins in synapse damage (Koo, Project 3). This Center will continue to maintain extremely strong Clinical and Neuropathological Cores. The Clinical Core will continue to longitudinally characterize a cohort of approximately 500 subjects to study early changes in cognition and semantic memory, and to provide other investigators and the San Diego community as a whole with a well characterized clinical cohort of both Caucasian and Hispanic volunteers. The Clinical Core will also recruit subjects and controls to support the special needs of many of the individual projects. The Center will also continue its participation in collaborative projects with other ADCs funded through the NACC or directly from NIA. Subjects will also participate in multi-center drug trials. Data derived from subjects will be used in collaborative research. In addition we will continue to carry out detailed clinicopathological correlations in Alzheimer's disease and other related neurodegenerative diseases: Lewy Body Variant of AD and fronto-temporal dementia. The Neuropath Core has taken a lead role in this endeavor. The Center as a whole will continue to provide brain tissue, plasma, serum, DNA, and cerebrospinal fluid to investigators upon request. The ADRC provides a setting to facilitate research training of investigators and will transfer information to the professional and lay communities through our mini- residency program, conferences and other educational activities. The Data Management and Biostatistics Core will continue to provide statistical design and analysis services to ADRC investigators, prepare the minimum data set for submission to the NACC, as well as coordinate the entry, quality control, management and analysis of data generated by the Clinical and Neuropathology Cores.